CRTH2 is a G-protein-coupled chemoattractant receptor, expressed on Th2 cells and eosinophilic granulocytes. Th2-polarization has been observed in allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis. Th2 cells generate Th2 cells factors, such as IL-4, IL-5 and IL-3, to regulate allergic diseases. In allergic diseases, these Th2 cells factors directly or indirectly induce immigration, activation, priming and prolonged survival of effector cells, such as eosinophilic granulocytes and basophilic granulocytes.
PGD2 (prostaglandin D2), a ligand for CRTH2, is produced from mast cells and other important effector cells in allergic diseases. In human cells, PGD2 induces immigration and activation of Th2 cells, eosinophilic granulocytes and basophilic via CRTH2. Therefore, antagonists inhibiting the combination of CRTH2 and PGD2 should be useful for the treatment of Th2-dependent allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis. It is reported that antagonists of CRTH2 receptors are also useful for the treatment of other eosinophilic granulocytes-related diseases such as Churg-Strauss syndrome and nasal sinusitis.
Conventionally, as CRTH2 inhibitors, indolyl acetic acid derivatives (see WO2005/019171, incorporated herein by reference), phenoxy acetic acid derivatives (see WO2005/115382, incorporated herein by reference), pyrimidinyl acetic acid derivatives (see WO2004/096777, incorporated herein by reference), di-fused ring derivatives (see CN103373996, incorporated herein by reference), isoquinoline derivatives (WO2010/074244, incorporated herein by reference) and the like have been reported.